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Surgical management of Cushing's syndrome
Biomed & Pharmacother 2000 ; 54 Suppl l : 140-5 © 2000 t~ditions scientifiques et m6dicales Elsevier SAS. All rights reserved
Mini review
Surgical management of Cushing's syndrome T. Imai*, T. Kikumori, H. Funahashi, A. Nakao Department of Surgen" 11, Nagoya UniversiO, School of Medicine, 65 Tsurumai-cho. Showa-ku, Nagoya 466-8550, Japan
Summary - Patients with Cushing's syndrome (137 total) who underwent adrenalectomy from 1957 through 1999 were reviewed for survival and complications. Of the 137 patients, 83 had adrenocortical adenoma, 30 Cushing's disease, seven primary pigmented nodular adrenocortical disease (PPNAD), eight adrenocorticotropin (ACTH)-independent macronodular hyperplasia, five adrenocortical carcinoma, and four ectopic ACTH syndromes. Seventy-eight patients with adrenocortical adenoma are alive, and their survival rate was equal to the age-matched control population, when patients who died of postoperative complications were excluded. Of the patients with Cushing's disease, 20 are alive, and ten of 16 patients (63%) who were followed and evaluated, had skin pigmentation. Four of 16 patients (25%) developed Nelson's syndrome. Five PPNAD patients and six with ACTH-independent macronodular hyperplasia are alive. All five adrenocortical carcinoma patients and four with ectopic ACTH syndrome died within two years after operation. The prognosis for patients with adrenocortical adenoma after unilateral adrenalectomy is excellent, though it is important to avoid operative complications. The rapid disappearance of signs and symptoms of glucocorticoid excess after total adrenalectomy is assured, and the prognosis is satisfactory under careful glucocorticoid replacement, making total adrenalectomy an alternative treatment for Cushing's disease. © 2000 Editions scientifiques et m~dicales Elsevier SAS adrenalectomy / Cushing's syndrome / follow-up
Cushing's syndrome is caused by hypersecretion of adrenocorticotropin (ACTH) (ACTH-dependent Cushing's syndrome) or by primary adrenal hypersecretion of glucocorticoids (ACTH-independent Cushing's syndrome). Surgical management of Cushing's syndrome by means of adrenalectomy is primarily indicated in ACTHindependent Cushing's syndrome, and for some instances of ACTH-dependent Cushing's syndrome. Since synthetic glucocorticoids became available for therapeutic use for the first time, adrenalectomy has provided a safe and reliable method of treating patients with Cushing's syndrome [32]. In the two decades following its introduction, the treatment of choice was adrenalectomy for Cushing's syndrome of either pituitary or adrenal origin. Thereafter, trans-sphenoidal micropituitary dissection supplanted total adrenalectomy as the preferred treatment for Cushing's disease [15]. Adrenalectomy is now used principally for patients with primary adrenal disease, occult ectopic ACTH syndrome, or pituitary disease that is refractory to other treatments. More than 70% of Cushing's syndrome is classified as Cushing's disease in Europe [ 11,22, 46] and the U S A
* Correspondence and reprints.
[14], whereas in Japan, 243 cases among 477 (50.9%) with Cushing's syndrome were caused by adrenal adenoma according to a survey conducted between 1982 to 1986 by the Japanese Ministry of Health and Welfare [7]. Among the other primary adrenocortical disorders such as nodular hyperplasia and adrenal carcinoma, approximately 60% of the patients with Cushing's syndrome in Japan were given adrenal surgery as the primary treatment. The pathological distribution of Cushing's syndrome is different among nations, and adrenal surgery is the most widespread form of treatment for Cushing's syndrome in Japan. This report will review our experience with adrenalectomy for Cushing's syndrome. The results of long-term follow-up and the current role of adrenalectomy for Cushing's syndrome are discussed.
PATIENTS AND METHODS From 1957 through 1999, 137 patients underwent adrenal exploration with the diagnosis of Cushing's syndrome at the Department of Surgery II, Nagoya University School of Medicine. On the basis of histologic and clinical findings related to the initial adrenal operation, patients were divided into the following subgroups: ACTH-dependent
Surgical management of Cushing's syndrome
141 s
Table I. Pathological distribution, sex, and prognosis of Cushing's syndrome.
Pathological diagnosis
Male
Female
Total
Alive
Dead
Unknown
ACTH-dependent Cushing's syndrome Cushing's disease Ectopic ACTH syndrome
9 2
21 2
30 4
20 0
8 4
2 0
ACTH-independent Cushing's syndrome Adrenocortical adenoma PPNAD ACTH-independent macronodular hyperplasia Adrenocortical carcinoma
8 1 3 3
75 6 5 2
83 7 8 5
78 5 6 0
5 2 2 5
0 0 0 0
Total
26
111
137
109
26
2
Cushing's syndrome: a) Cushing's disease, b) ectopic ACTH syndrome; ACTH-independent Cushing's syndrome: c) adrenocortical adenoma, d) primary pigmented nodular adrenocortical disease (PPNAD) [12], e) ACTHindependent macronodular hyperplasia [30], and f) adrenocortical carcinoma (table I).
ACTH-dependent Cushing'ssyndrome Thirty patients underwent bilateral total adrenalectomy for Cushing's disease before 1980 [5]. The follow-up was from 14 to 36 years (median = 25.8 years). Four patients underwent bilateral total adrenalectomy for ectopic ACTH syndrome. However, the original ACTHproducing tumors were far advanced, and all patients died within one year.
ACTH-independentCushing'ssyndrome Eighty-three patients underwent unilateral adrenalectomy for benign adrenocortical adenoma. The follow-up was from one to 38 years (median = 13.1 years). Seven patients underwent adrenal resection for PPNAD [35]. The follow-up was from two to 29 years (median = 18.9 years). Eight patients underwent adrenal resection for ACTHindependent macronodular hyperplasia [39]. The follow-up was from one to 21 years (median = 10.8 years). Five patients underwent adrenal resection for adrenocortical cancer. However, the adrenal tumors were far advanced, and all patients died within two years. The patients were followed up to December 1999 by patient visits, correspondence, phone calls, physicians' letters, or autopsy reports. Information on some patients was obtained by family register or review of death certificates (permission number 6560, from the Ministry of Justice in Japan) in 1994 [16]. Of the 137 patients, two patients with Cushing's disease could not be traced, but follow-up data on the other 135 patients were obtained.
Glucocorticoidreplacement From the day of the operation, the patients were treated with 100 mg hydrocortisone sodium succinate (Solu-Cortef, Pharmacia-Upjohn, Tokyo) administered intravenously at the time of ligation of adrenal vein and every eight hours after adrenalectomy. The dose was tapered to 100 mg and 50 mg every eight hours on postoperative days 2 and 3, respectively. Then the hydrocortisone tablets (Cortril, Pfizer, Tokyo) were administered orally, and the dose was tapered to 40 rag/day for one week. The patient's clinical condition determines how much further to taper the dose to parallel clinical improvement. Most patients have been exposed to endogenous hypercortisolism for many years, and abrupt postoperative institution of replacement doses of glucocorticoids results in significant withdrawal symptoms. Typically, patients are dismissed from the hospital on hydrocortisone 10 mg orally in the morning. RESULTS The survival of patients with Cushing's syndrome is shown infigure 1 [20]. The results are grouped according to the final pathologic diagnosis.
ACTH-dependent Cushing'ssyndrome Cushing's disease Four patients with Cushing's disease died seven months, five, 14, and 24 years after adrenal surgery because of acute adrenocortical insufficiency due to inadequate replacement of glucocorticoid, sudden death from unknown factors, acute bronchitis, and psychosis, respectively (figure 1). Ten of 16 (63%) patients who could be evaluated objectively had facial and finger pigmentation, and four of them (25%) with severe pigmentation were diagnosed as having Nelson's syndrome and underwent a pituitary operation [28]. All surviving patients have received oral glucocorticoid
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MN
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0.5 0.4 0.3 0.2 ....
0.1
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0.0
0
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I
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I
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10
15
20
25
30
35
40
Years Figure 1. Observed survival curves of Cushing's syndrome. Vertical bars indicate censored observations. The following are the pathological subgroups. A: Adrenocortical adenoma; H: Cushing's disease; PN: PPNAD; MN: ACTH-independent macronodular hyperplasia; Ca + E: Adrenocortical carcinoma and ectopic ACTH syndrome. replacement therapy, and at the time of survey, none of the patients had Cushing's syndrome.
ACTH-independent Cushing's syndrome
Adrenocortical adenoma Seventy-eight of 83 patients with adrenocortical adenomas are alive. Four of five patients died within three months after adrenalectomy, the causes of death being pulmonary complication, coagulopathy, and adrenal insufficiency. One patient with adrenocortical adenoma died nine years after adrenal surgery from cerebral hemorrhage. At autopsy, the pituitary and remaining adrenal gland were normal. Survival in patients with adrenocortical adenomas paralleled the expected survival of the control population, when patients who died from postoperative complications were excluded. Cushing's syndrome recurred in two patients due to another contra-lateral adrenocortical adenoma 20 years after the first adrenalectomy. One of these patients received contra-lateral partial adrenalectomy, had pathologically proven adrenocortical adenoma, and the syndrome remitted [18]. The other patient has been on medications.
PPNAD Two PPNAD patients died 1.5 and 13 years after total adrenalectomy from insufficient replacement of gluco-
corticoid and sudden death due to unknown factors, respectively. Another five patients are well under oral glucocorticoid replacement and none of them has skin pigmentation or pituitary abnormality. The average age of these patients at the time of surgery was younger when compared with the other groups (18.2 in this group vs 34.3 in other groups). One patient with PPNAD succeeded in delivering a child with glucocorticoid replacement 14 years after total adrenalectomy.
ACTH.independent macronodular hyperplasia Two patients of ACTH-independent macronodular hyperplasia died eight days and 11 years after total adrenalectomy because of incisional hernia and cerebellar neoplasm, respectively. Six patients are outpatients of our hospital, and they do not have skin pigmentation. One patient had aseptic necrosis of head of the femur two years after total adrenalectomy.
Operative approach In the 1950s and 1960s, the operative approach was abdominal transperitoneal incision. After the scowl experience with abdominal incision, such as incisional hernia, incidental splenectomy, and postoperative hemorrhage, postero-lateral incision was chosen. After 1981, the lateral approach was the preferred type of incision for either unilateral or bilateral adrenalectomy. Although it was necessary to change the position for a
Surgical managementof Cushing's syndrome bilateral adrenalectomy using a lateral incision, with great care in positioning and moving the patient to avoid possible fractures, this approach was superior to the others as reported earlier [33, 34]. Since 1996, lateral transabdominal laparoscopic adrenalectomy has been the treatment of choice for benign adrenal neoplasms in our institution [17]. Eleven patients with Cushing's syndrome underwent laparoscopic adrenalectomy, nine of which were adrenocortical adenoma, one was PPNAD, and one was ACTH-independent macronodular hyperplasia. DISCUSSION Without recognition and proper treatment, Cushing's syndrome results in high rates of morbidity and mortality. Untreated patients have a five-year survival rate of 50%, with most deaths resulting from infection or cerebrovascular disease [31]. In the 1950s, the treatment of choice for Cushing's syndrome was bilateral adrenalectomy, which markedly increased survival compared to untreated patients [45]. The prognosis of Cushing's syndromes treated by adrenalectomy was very different between the subgroups [44]. As shown in figure 1, the prognosis for adrenocortical adenoma was excellent. Without early operative death, the cumulative survival rate is the same as in the age-matched group. At the time of the survey, all patients with unilateral adrenocortical adenoma no longer underwent glucocorticoid replacement, and the signs and symptoms of Cushing's syndrome had disappeared. The quality of life in this group is excellent. Patients with hypercortisolism, whether the cause is endogenous or exogenous, have traditionally been regarded as at high risk when undergoing any surgical procedure. The principal risks have been those related to decreased wound-healing capabilities (decreased fibroblastic activity) and an increased risk of infection (decreased immunologic competence). One must be very careful not to lose a patient due to operative complications. The prognosis for Cushing's disease is favorable (figure 1). Nelson's syndrome is a late complication of total adrenalectomy for Cushing's disease and lifetime glucocorticoid replacement is necessary. Out of the 20 patients with Cushing's disease who are alive, 16 could be assessed objectively regarding skin pigmentation. Pigmentation developed some time after adrenalectomy in ten out of 16 patients (63%). Four patients (25%) had pituitary tumors (Nelson's syndrome) and underwent a pituitary operation. The incidence of pigmentation and Nelson's syndrome were reported to be 0 to 55%, and 0 to 46%, respectively [4,
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19, 25, 26, 29]. The incidence is higher in infants [41]. In our patients, only two of 16 patients were under 20 years of age at the time of adrenalectomy, and now one has pigmentation and another underwent a pituitary operation for Nelson's syndrome. Kemink et al. reported that the patient's age is a simple predictive factor for the development of Nelson's syndrome after total adrenalectomy for Cushing's disease [21 ]. In our series, all four patients who developed Nelson's syndrome were younger than 35 years of age at the time of adrenalectomy. Pigmentation and Nelson's syndrome are one of the major disadvantages of total adrenalectomy for Cushing's disease. However, after the successful removal of pituitary tumors, the pigmentation disappeared rapidly. Insufficient glucocorticoid replacement was the cause of late death in three patients after bilateral total adrenalectomy. Education about glucocorticoid replacement is important for patients as well as for family members and for the primary-care physician. Given the good results of the trans-sphenoidal operation [ 13, 24, 27, 40, 42], many patients with Cushing's disease will not require adrenalectomy. However, when indicated, adrenalectomy is safe. The 'cure' rate of trans-sphenoidal operation for Cushing's disease has been reported to be 70-92%. A recurrence rate has been reported to vary up to 49%; the longer the period of follow-up, the higher the incidence of recurrence [8, 40]. Those patients in which the disease recurs or the unimproved patients are candidates for bilateral total adrenalectomy [48]. Bilateral adrenalectomy assumes a well-defined role in the treatment of Cushing's disease: 1) in cases in which pituitary treatment has been unsuccessful; or 2) pituitary surgery is a technical impossibility; and 3) in the presence of a rapidly worsening syndrome of hypercortisolism that cannot be adequately controlled with drug therapy because the latter is not tolerated by the patient and for which a clear-cut diagnosis cannot be made. Patients who undergo a pituitary operation primarily, or receive pituitary irradiation, are less likely to develop Nelson's syndrome after total adrenalectomy [19]. The rapid cure of Cushing's syndrome after total adrenalectomy is assured and the prognosis under careful glucocorticoid replacement is satisfactory [2, 3]. The prognosis in cases of nodular hyperplasia was relatively poor (figure 1). Of 15 patients who showed nodular enlargement of adrenal glands and ACTHindependent glucocorticoid excess, seven were classified as having PPNAD based on the macroscopic and microscopic findings of the resected adrenals. The average age was younger than other patients. The
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macroscopic and microscopic findings were in agreement with PPNAD, and immunohistochemical and in situ hybridization analyses of steroidogenic enzymes were previously reported [36]. The two patients with PPNAD who died 1.5 and 13 years after adrenalectomy were not studied closely at the time of death, but sudden death from unknown factors might be related to the complications of PPNAD [37]. The other eight patients were not commonly classified as having macronodular adrenocortical disease [23, 47] or adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia (AIMAH) [ 1]. The prognosis was very poor for patients with ectopic ACTH syndrome and adrenocortical carcinoma (figure 1). All of the patients with ectopic ACTH syndrome and adrenocortical carcinoma were in the far advanced stages when diagnosed. Despite various treatments, all patients died within two years. It is interesting to find the predominance of women in most of the categories: C u s h i n g ' s disease, 70%; adrenocortical adenoma, 90%; PPNAD, 86%; and ACTH-independent macronodular hyperplasia, 63%. These findings of female predominance are in agreement with the ones reported by van Heerden et al. [43]. A uniform elevation in factor VIII levels was demonstrated in 15 patients with Cushing's syndrome, levels that normalized three to four months after operation [6]. Sjoberg et al. found postoperative thromboembolic occurrences in seven of 19 patients with Cushing's syndrome and demonstrated a positive correlation between the increase in factor VII1 and the severity of the hypercortisolism [38]. Both reports suggested the prophylactic heparinization in patients undergoing operation for hypercortisolism. We have made routine use of intraoperative venous compression of the patients' legs, and early and vigorous ambulation, instead of systemic heparinization. Since October 1995, we have employed transabdominal lateral laparoscopic adrenalectomy for the treatment of Cushing's syndrome [9]. Cushing's syndrome is ideally suited for laparoscopic excision as most adrenal disorders are small and pathologically benign. The benefits of laparoscopic adrenalectomy include decreased operative blood loss, reduced analgesic requirements, shorter hospital stay and recovery time, and fewer late i n c i s i o n a l c o m p l i c a t i o n s [10, 17]. Laparoscopic adrenalectomy obtained aesthetically good results, as conventional adrenal surgery requires a relatively large incision because the adrenal glands are located deep in the retroperitoneal space. The relative risks in Cushing's syndrome have been those related to decreased wound-healing capabilities and an increased
risk of infection. Laparoscopic procedure has the advantages in those risks, especially in obese and fragile patients with Cushing's syndrome. The safety and efficacy of this procedure have been widely accepted. With the improvements of image diagnosis, anesthesia, perioperative care, and the operative approach, adrenalectomy is a safe and reliable treatment for Cushing's syndrome. In conclusion, adrenalectomy continues to play an important role in the treatment of Cushing's syndrome and is the treatment of choice for an adrenal adenoma, adrenocortical carcinoma, and primary adrenocortical hyperplasia. Furthermore, in selected cases, bilateral total adrenalectomy continues to be an alternative treatment for either Cushing's disease or ectopic ACTH syndrome.
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13 Guilhaume B, Thomsen M, Bricaire C, Vila PE, Olivier L, Racadot J, et al. Transsphenoidal pituitary surgery for the treatment of Cushing's disease: results in 64 patients and longterm follow-up studies. J Clin Endocrinol Metab 1988 ; 66 : 1056-64. 14 Hamberger B, Russell CF, van Heerden JA, ReMine WH, Northcutt RC, Sheedy PF, et al. Adrenal surgery: trends during the seventies. Am J Surg 1982 ; 144 : 523-6. 15 Hardy J. Transsphenoidal microsurgery of the normal and pathological pituitary. Clin Neurosurg 1969 ; 16 : 185-217. 16 Imai T, Funahashi H, Tanaka Y, Tobinaga J, Wada M, MoritaMatsuyama T, et al. Adrenalectomy for treatment of Cushing's syndrome: results in 122 patients and long-term follow-up studies. World J Surg 1996 ; 20 : 781-6. 17 Imai T, Kikumori T, Ohiwa M, Mase T, Funahashi H. A case controlled study of laparoscopic compared to open lateral adrenalectomy. Am J Surg 1999 ; 178 : 50-3. 18 Imai T, TanakaY, Kikumori T, Ohiwa M, Matsuura N, Mase T, et al. Laparoscopic partial adrenalectomy. Surg Endosc 1999 ; 13 : 343-5. 19 Jenkins P, Trainer PJ, Plowman PN, Shand WS, Grossman AB, Wass JA, et al. The long-term outcome after adrenalectomy and prophylactic pituitary radiotherapy in adrenocorticotropindependent Cushing's syndrome. J Clin Endocrinol Metab 1995 ; 80 : 165-71. 20 Kaplan E, Meier E Non-parametric estimation from incomplete observations. J Am Statis Assoc 1958 ; 53 : 457-81. 21 Kemink L, Pieters G, Hermus A, Smals A, Kloppenborg E Patient's age is a simple predictive factor for the development of Nelson's syndrome after total adrenalectomy for Cushing's disease. J Clin Endocrinol Metab 1994 ; 79 : 887-9. 22 Kuhn J, Proeschel ME Seurin D J, Bertagna XY, Luton JP, Girard FL. Comparative assessment of ACTH and lipotropin plasma levels in the diagnosis and follow-up of patients with Cushing's syndrome: a study of 210 cases. Am J Med 1989 ; 86 : 678-84. 23 Malchoff C, Rosa J, DeBold CR, Kozol RA, Ramsby GR, Page DL, et al. Adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia: an unusual cause of Cushing's syndrome. J Clin Endocrinol Metab 1989 ; 68 : 855-60. 24 Mampalam T, Tyrrell JB, Wilson CB. Transsphenoidal microsurgery for Cushing's disease. A report of 216 cases. Ann Intern Med 1988 ; 109 : 487-93. 25 Manolas K, Farmer HM, Wilson HK, Kennedy AL, Joplin GF, Montgomery DAD, et al. The pituitary before and after adrenalectomy for Cushing's syndrome. World J Surg 1984 ; 8 : 374-87. 26 McCance D, Gordon DS, Fannin TF, Hadden DR, Kennedy L, Sheridan B, et al. Assessment of endocrine function after transsphenoidal surgery for Cushing's disease. Clin Endocrinol 1993 ; 38 : 79-86. 27 Nakane T, Kuwayama A, Watanabe M, Takahashi T, Kato T, Ichihara K, et al. Long-term results of transsphenoidal adenomectomy in patients with Cushing's disease. Neurosurg 1987 ; 21 : 218-22. 28 Nelson D, Meakin JW, Dealy JB, Matson DD, Emerson K, Thorn GW. ACTH-producing tumor of the pituitary gland. N Engl J Med 1958 ; 259 : 161-4. 29 Orth D, Liddle GW. Results of treatment in 108 patients with Cushing's syndrome. N Engl J Med 1971 ; 285 : 243-7.
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30 Perry R, Nieman LK, Cutler GB, Chrousos GR Loriaux DL, Doppman JL, et al. Primary adrenal causes of Cushing's syndrome. Diagnosis and surgical management. Ann Surg 1989 ; 210 : 59-68. 31 Plotz C, Knowlton AI, Ragan C. The natural history of Cushing's syndrome. Am J Med 1952 ; 13 : 597-614. 32 Priestley J, Aprague RG, Walters W, Salassa RM. Subtotal adrenalectomy for Cushing's syndrome: a preliminary report of 29 cases. Ann Surg 1951 ; 134 : 464-75. 33 Proye C, Huart JY, Cuvillier XD, Assez NM, Gambardella B, Carnaille BM. Safety of the posterior approach in adrenal surgery: experience in 105 cases. Surgery 1993 ; 114 : 1126-31. 34 Russell C, Hamberger B, van Heerden JA, Edis AJ, Ilstrup DM. Adrenalectomy: anterior or posterior approach? Am J Surg 1982 ; 144 : 322-4. 35 Sarlis N, Chrousos GP, Doppman JL, Carney JA, Stratakis CA. Primary pigmented nodular adrenocortical disease: reevaluation of a patient with carney complex 27 years after unilateral adrenalectomy. J Clin Endocrinol Metab 1997 ; 82 : 1274-8. 36 Sasano H, Miyazaki S, Sawai T, Sasano N, Nagura H, Funahashi H, et al. Primary pigmented nodular adrenocortical disease (PPNAD): immunohistochemical and in situ hybridization analysis of steroidogenic enzymes in eight cases. Mod Pathol 1992 ; 5 : 23-9. 37 Shenoy B, Carpenter PC, Carney JA. Bilateral primary pigmented nodular adrenocortical disease. Rare cause of the Cushing's syndrome. Am J Surg Pathol 1984 ; 8 : 335-44. 38 Sjoberg H, Blomback M, Granberg PO. Thromboembolic complications, heparin treatment and increase in coagulation factors in Cushing's syndrome. Acta Med Scand 1976 ; 199 : 95-8. 39 Swain J, Grant CS, Schlinkert RT, Thompson GB, van Heerden JA, Lloyd RV, et al. Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation. Arch Surg 1998 ; 133 : 541-6. 40 Tahir A, Sheeler LR. Recurrent Cushing's disease after transsphenoidal surgery. Arch Intern Med 1992 ; 152 : 977-81. 41 Thomas C, Smith AT, Benson M, Griffith J. Nelson's syndrome after Cushing's disease in childhood: a continuing problem. Surgery 1984 ; 96 : 1067-77. 42 Tindall G, Herring CJ, Clark RV, Adams DA, Watts NB. Cushing's disease: results of transsphenoidal microsurgery with emphasis on surgical failures. J Neurosurg 1990 ; 72 : 363-9. 43 van Heerden J, Young WE Grant CS, Carpenter PC. Adrenal surgery for hypercortisolism - surgical aspects. Surgery 1995 ; 117 : 466-72. 44 Watson R, van Heerden JA, Northcutt RC, Grant CS, Ilstrup DM. Results of adrenal surgery for Cushing's syndrome: 10 years' experience. World J Surg 1986 ; 10 : 531-8. 45 Welbourn R, Montgomery DAD, Kennedy TL. The natural history of treated Cushing's syndrome. Br J Surg 1971 ; 58 : 1-16. 46 Welbourn R. Some aspects of adrenal surgery. Br J Surg 1980 ; 67 : 723-7. 47 Zeiger M, Nieman LK, Cutler GB, Chrousos GP, Doppman JL, Travis WD, et al. Primary bilateral adrenocortical causes of Cushing's syndrome. Surgery 1991 ; 110:1106-15. 48 Zeiger M, Fraker DL, Pass HI, Nieman LK, Cutler GB, Chrousos GR et al. Effective reversibility of the signs and symptoms of hypercortisolism by bilateral adrenalectomy. Surgery 1993 ; 114 : 1138-43.
Mini review
Surgical management of Cushing's syndrome T. Imai*, T. Kikumori, H. Funahashi, A. Nakao Department of Surgen" 11, Nagoya UniversiO, School of Medicine, 65 Tsurumai-cho. Showa-ku, Nagoya 466-8550, Japan
Summary - Patients with Cushing's syndrome (137 total) who underwent adrenalectomy from 1957 through 1999 were reviewed for survival and complications. Of the 137 patients, 83 had adrenocortical adenoma, 30 Cushing's disease, seven primary pigmented nodular adrenocortical disease (PPNAD), eight adrenocorticotropin (ACTH)-independent macronodular hyperplasia, five adrenocortical carcinoma, and four ectopic ACTH syndromes. Seventy-eight patients with adrenocortical adenoma are alive, and their survival rate was equal to the age-matched control population, when patients who died of postoperative complications were excluded. Of the patients with Cushing's disease, 20 are alive, and ten of 16 patients (63%) who were followed and evaluated, had skin pigmentation. Four of 16 patients (25%) developed Nelson's syndrome. Five PPNAD patients and six with ACTH-independent macronodular hyperplasia are alive. All five adrenocortical carcinoma patients and four with ectopic ACTH syndrome died within two years after operation. The prognosis for patients with adrenocortical adenoma after unilateral adrenalectomy is excellent, though it is important to avoid operative complications. The rapid disappearance of signs and symptoms of glucocorticoid excess after total adrenalectomy is assured, and the prognosis is satisfactory under careful glucocorticoid replacement, making total adrenalectomy an alternative treatment for Cushing's disease. © 2000 Editions scientifiques et m~dicales Elsevier SAS adrenalectomy / Cushing's syndrome / follow-up
Cushing's syndrome is caused by hypersecretion of adrenocorticotropin (ACTH) (ACTH-dependent Cushing's syndrome) or by primary adrenal hypersecretion of glucocorticoids (ACTH-independent Cushing's syndrome). Surgical management of Cushing's syndrome by means of adrenalectomy is primarily indicated in ACTHindependent Cushing's syndrome, and for some instances of ACTH-dependent Cushing's syndrome. Since synthetic glucocorticoids became available for therapeutic use for the first time, adrenalectomy has provided a safe and reliable method of treating patients with Cushing's syndrome [32]. In the two decades following its introduction, the treatment of choice was adrenalectomy for Cushing's syndrome of either pituitary or adrenal origin. Thereafter, trans-sphenoidal micropituitary dissection supplanted total adrenalectomy as the preferred treatment for Cushing's disease [15]. Adrenalectomy is now used principally for patients with primary adrenal disease, occult ectopic ACTH syndrome, or pituitary disease that is refractory to other treatments. More than 70% of Cushing's syndrome is classified as Cushing's disease in Europe [ 11,22, 46] and the U S A
* Correspondence and reprints.
[14], whereas in Japan, 243 cases among 477 (50.9%) with Cushing's syndrome were caused by adrenal adenoma according to a survey conducted between 1982 to 1986 by the Japanese Ministry of Health and Welfare [7]. Among the other primary adrenocortical disorders such as nodular hyperplasia and adrenal carcinoma, approximately 60% of the patients with Cushing's syndrome in Japan were given adrenal surgery as the primary treatment. The pathological distribution of Cushing's syndrome is different among nations, and adrenal surgery is the most widespread form of treatment for Cushing's syndrome in Japan. This report will review our experience with adrenalectomy for Cushing's syndrome. The results of long-term follow-up and the current role of adrenalectomy for Cushing's syndrome are discussed.
PATIENTS AND METHODS From 1957 through 1999, 137 patients underwent adrenal exploration with the diagnosis of Cushing's syndrome at the Department of Surgery II, Nagoya University School of Medicine. On the basis of histologic and clinical findings related to the initial adrenal operation, patients were divided into the following subgroups: ACTH-dependent
Surgical management of Cushing's syndrome
141 s
Table I. Pathological distribution, sex, and prognosis of Cushing's syndrome.
Pathological diagnosis
Male
Female
Total
Alive
Dead
Unknown
ACTH-dependent Cushing's syndrome Cushing's disease Ectopic ACTH syndrome
9 2
21 2
30 4
20 0
8 4
2 0
ACTH-independent Cushing's syndrome Adrenocortical adenoma PPNAD ACTH-independent macronodular hyperplasia Adrenocortical carcinoma
8 1 3 3
75 6 5 2
83 7 8 5
78 5 6 0
5 2 2 5
0 0 0 0
Total
26
111
137
109
26
2
Cushing's syndrome: a) Cushing's disease, b) ectopic ACTH syndrome; ACTH-independent Cushing's syndrome: c) adrenocortical adenoma, d) primary pigmented nodular adrenocortical disease (PPNAD) [12], e) ACTHindependent macronodular hyperplasia [30], and f) adrenocortical carcinoma (table I).
ACTH-dependent Cushing'ssyndrome Thirty patients underwent bilateral total adrenalectomy for Cushing's disease before 1980 [5]. The follow-up was from 14 to 36 years (median = 25.8 years). Four patients underwent bilateral total adrenalectomy for ectopic ACTH syndrome. However, the original ACTHproducing tumors were far advanced, and all patients died within one year.
ACTH-independentCushing'ssyndrome Eighty-three patients underwent unilateral adrenalectomy for benign adrenocortical adenoma. The follow-up was from one to 38 years (median = 13.1 years). Seven patients underwent adrenal resection for PPNAD [35]. The follow-up was from two to 29 years (median = 18.9 years). Eight patients underwent adrenal resection for ACTHindependent macronodular hyperplasia [39]. The follow-up was from one to 21 years (median = 10.8 years). Five patients underwent adrenal resection for adrenocortical cancer. However, the adrenal tumors were far advanced, and all patients died within two years. The patients were followed up to December 1999 by patient visits, correspondence, phone calls, physicians' letters, or autopsy reports. Information on some patients was obtained by family register or review of death certificates (permission number 6560, from the Ministry of Justice in Japan) in 1994 [16]. Of the 137 patients, two patients with Cushing's disease could not be traced, but follow-up data on the other 135 patients were obtained.
Glucocorticoidreplacement From the day of the operation, the patients were treated with 100 mg hydrocortisone sodium succinate (Solu-Cortef, Pharmacia-Upjohn, Tokyo) administered intravenously at the time of ligation of adrenal vein and every eight hours after adrenalectomy. The dose was tapered to 100 mg and 50 mg every eight hours on postoperative days 2 and 3, respectively. Then the hydrocortisone tablets (Cortril, Pfizer, Tokyo) were administered orally, and the dose was tapered to 40 rag/day for one week. The patient's clinical condition determines how much further to taper the dose to parallel clinical improvement. Most patients have been exposed to endogenous hypercortisolism for many years, and abrupt postoperative institution of replacement doses of glucocorticoids results in significant withdrawal symptoms. Typically, patients are dismissed from the hospital on hydrocortisone 10 mg orally in the morning. RESULTS The survival of patients with Cushing's syndrome is shown infigure 1 [20]. The results are grouped according to the final pathologic diagnosis.
ACTH-dependent Cushing'ssyndrome Cushing's disease Four patients with Cushing's disease died seven months, five, 14, and 24 years after adrenal surgery because of acute adrenocortical insufficiency due to inadequate replacement of glucocorticoid, sudden death from unknown factors, acute bronchitis, and psychosis, respectively (figure 1). Ten of 16 (63%) patients who could be evaluated objectively had facial and finger pigmentation, and four of them (25%) with severe pigmentation were diagnosed as having Nelson's syndrome and underwent a pituitary operation [28]. All surviving patients have received oral glucocorticoid
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Survival 1.o "I -! . . . . . . . . . _, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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0.5 0.4 0.3 0.2 ....
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10
15
20
25
30
35
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Years Figure 1. Observed survival curves of Cushing's syndrome. Vertical bars indicate censored observations. The following are the pathological subgroups. A: Adrenocortical adenoma; H: Cushing's disease; PN: PPNAD; MN: ACTH-independent macronodular hyperplasia; Ca + E: Adrenocortical carcinoma and ectopic ACTH syndrome. replacement therapy, and at the time of survey, none of the patients had Cushing's syndrome.
ACTH-independent Cushing's syndrome
Adrenocortical adenoma Seventy-eight of 83 patients with adrenocortical adenomas are alive. Four of five patients died within three months after adrenalectomy, the causes of death being pulmonary complication, coagulopathy, and adrenal insufficiency. One patient with adrenocortical adenoma died nine years after adrenal surgery from cerebral hemorrhage. At autopsy, the pituitary and remaining adrenal gland were normal. Survival in patients with adrenocortical adenomas paralleled the expected survival of the control population, when patients who died from postoperative complications were excluded. Cushing's syndrome recurred in two patients due to another contra-lateral adrenocortical adenoma 20 years after the first adrenalectomy. One of these patients received contra-lateral partial adrenalectomy, had pathologically proven adrenocortical adenoma, and the syndrome remitted [18]. The other patient has been on medications.
PPNAD Two PPNAD patients died 1.5 and 13 years after total adrenalectomy from insufficient replacement of gluco-
corticoid and sudden death due to unknown factors, respectively. Another five patients are well under oral glucocorticoid replacement and none of them has skin pigmentation or pituitary abnormality. The average age of these patients at the time of surgery was younger when compared with the other groups (18.2 in this group vs 34.3 in other groups). One patient with PPNAD succeeded in delivering a child with glucocorticoid replacement 14 years after total adrenalectomy.
ACTH.independent macronodular hyperplasia Two patients of ACTH-independent macronodular hyperplasia died eight days and 11 years after total adrenalectomy because of incisional hernia and cerebellar neoplasm, respectively. Six patients are outpatients of our hospital, and they do not have skin pigmentation. One patient had aseptic necrosis of head of the femur two years after total adrenalectomy.
Operative approach In the 1950s and 1960s, the operative approach was abdominal transperitoneal incision. After the scowl experience with abdominal incision, such as incisional hernia, incidental splenectomy, and postoperative hemorrhage, postero-lateral incision was chosen. After 1981, the lateral approach was the preferred type of incision for either unilateral or bilateral adrenalectomy. Although it was necessary to change the position for a
Surgical managementof Cushing's syndrome bilateral adrenalectomy using a lateral incision, with great care in positioning and moving the patient to avoid possible fractures, this approach was superior to the others as reported earlier [33, 34]. Since 1996, lateral transabdominal laparoscopic adrenalectomy has been the treatment of choice for benign adrenal neoplasms in our institution [17]. Eleven patients with Cushing's syndrome underwent laparoscopic adrenalectomy, nine of which were adrenocortical adenoma, one was PPNAD, and one was ACTH-independent macronodular hyperplasia. DISCUSSION Without recognition and proper treatment, Cushing's syndrome results in high rates of morbidity and mortality. Untreated patients have a five-year survival rate of 50%, with most deaths resulting from infection or cerebrovascular disease [31]. In the 1950s, the treatment of choice for Cushing's syndrome was bilateral adrenalectomy, which markedly increased survival compared to untreated patients [45]. The prognosis of Cushing's syndromes treated by adrenalectomy was very different between the subgroups [44]. As shown in figure 1, the prognosis for adrenocortical adenoma was excellent. Without early operative death, the cumulative survival rate is the same as in the age-matched group. At the time of the survey, all patients with unilateral adrenocortical adenoma no longer underwent glucocorticoid replacement, and the signs and symptoms of Cushing's syndrome had disappeared. The quality of life in this group is excellent. Patients with hypercortisolism, whether the cause is endogenous or exogenous, have traditionally been regarded as at high risk when undergoing any surgical procedure. The principal risks have been those related to decreased wound-healing capabilities (decreased fibroblastic activity) and an increased risk of infection (decreased immunologic competence). One must be very careful not to lose a patient due to operative complications. The prognosis for Cushing's disease is favorable (figure 1). Nelson's syndrome is a late complication of total adrenalectomy for Cushing's disease and lifetime glucocorticoid replacement is necessary. Out of the 20 patients with Cushing's disease who are alive, 16 could be assessed objectively regarding skin pigmentation. Pigmentation developed some time after adrenalectomy in ten out of 16 patients (63%). Four patients (25%) had pituitary tumors (Nelson's syndrome) and underwent a pituitary operation. The incidence of pigmentation and Nelson's syndrome were reported to be 0 to 55%, and 0 to 46%, respectively [4,
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19, 25, 26, 29]. The incidence is higher in infants [41]. In our patients, only two of 16 patients were under 20 years of age at the time of adrenalectomy, and now one has pigmentation and another underwent a pituitary operation for Nelson's syndrome. Kemink et al. reported that the patient's age is a simple predictive factor for the development of Nelson's syndrome after total adrenalectomy for Cushing's disease [21 ]. In our series, all four patients who developed Nelson's syndrome were younger than 35 years of age at the time of adrenalectomy. Pigmentation and Nelson's syndrome are one of the major disadvantages of total adrenalectomy for Cushing's disease. However, after the successful removal of pituitary tumors, the pigmentation disappeared rapidly. Insufficient glucocorticoid replacement was the cause of late death in three patients after bilateral total adrenalectomy. Education about glucocorticoid replacement is important for patients as well as for family members and for the primary-care physician. Given the good results of the trans-sphenoidal operation [ 13, 24, 27, 40, 42], many patients with Cushing's disease will not require adrenalectomy. However, when indicated, adrenalectomy is safe. The 'cure' rate of trans-sphenoidal operation for Cushing's disease has been reported to be 70-92%. A recurrence rate has been reported to vary up to 49%; the longer the period of follow-up, the higher the incidence of recurrence [8, 40]. Those patients in which the disease recurs or the unimproved patients are candidates for bilateral total adrenalectomy [48]. Bilateral adrenalectomy assumes a well-defined role in the treatment of Cushing's disease: 1) in cases in which pituitary treatment has been unsuccessful; or 2) pituitary surgery is a technical impossibility; and 3) in the presence of a rapidly worsening syndrome of hypercortisolism that cannot be adequately controlled with drug therapy because the latter is not tolerated by the patient and for which a clear-cut diagnosis cannot be made. Patients who undergo a pituitary operation primarily, or receive pituitary irradiation, are less likely to develop Nelson's syndrome after total adrenalectomy [19]. The rapid cure of Cushing's syndrome after total adrenalectomy is assured and the prognosis under careful glucocorticoid replacement is satisfactory [2, 3]. The prognosis in cases of nodular hyperplasia was relatively poor (figure 1). Of 15 patients who showed nodular enlargement of adrenal glands and ACTHindependent glucocorticoid excess, seven were classified as having PPNAD based on the macroscopic and microscopic findings of the resected adrenals. The average age was younger than other patients. The
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macroscopic and microscopic findings were in agreement with PPNAD, and immunohistochemical and in situ hybridization analyses of steroidogenic enzymes were previously reported [36]. The two patients with PPNAD who died 1.5 and 13 years after adrenalectomy were not studied closely at the time of death, but sudden death from unknown factors might be related to the complications of PPNAD [37]. The other eight patients were not commonly classified as having macronodular adrenocortical disease [23, 47] or adrenocorticotropic hormone-independent bilateral adrenocortical macronodular hyperplasia (AIMAH) [ 1]. The prognosis was very poor for patients with ectopic ACTH syndrome and adrenocortical carcinoma (figure 1). All of the patients with ectopic ACTH syndrome and adrenocortical carcinoma were in the far advanced stages when diagnosed. Despite various treatments, all patients died within two years. It is interesting to find the predominance of women in most of the categories: C u s h i n g ' s disease, 70%; adrenocortical adenoma, 90%; PPNAD, 86%; and ACTH-independent macronodular hyperplasia, 63%. These findings of female predominance are in agreement with the ones reported by van Heerden et al. [43]. A uniform elevation in factor VIII levels was demonstrated in 15 patients with Cushing's syndrome, levels that normalized three to four months after operation [6]. Sjoberg et al. found postoperative thromboembolic occurrences in seven of 19 patients with Cushing's syndrome and demonstrated a positive correlation between the increase in factor VII1 and the severity of the hypercortisolism [38]. Both reports suggested the prophylactic heparinization in patients undergoing operation for hypercortisolism. We have made routine use of intraoperative venous compression of the patients' legs, and early and vigorous ambulation, instead of systemic heparinization. Since October 1995, we have employed transabdominal lateral laparoscopic adrenalectomy for the treatment of Cushing's syndrome [9]. Cushing's syndrome is ideally suited for laparoscopic excision as most adrenal disorders are small and pathologically benign. The benefits of laparoscopic adrenalectomy include decreased operative blood loss, reduced analgesic requirements, shorter hospital stay and recovery time, and fewer late i n c i s i o n a l c o m p l i c a t i o n s [10, 17]. Laparoscopic adrenalectomy obtained aesthetically good results, as conventional adrenal surgery requires a relatively large incision because the adrenal glands are located deep in the retroperitoneal space. The relative risks in Cushing's syndrome have been those related to decreased wound-healing capabilities and an increased
risk of infection. Laparoscopic procedure has the advantages in those risks, especially in obese and fragile patients with Cushing's syndrome. The safety and efficacy of this procedure have been widely accepted. With the improvements of image diagnosis, anesthesia, perioperative care, and the operative approach, adrenalectomy is a safe and reliable treatment for Cushing's syndrome. In conclusion, adrenalectomy continues to play an important role in the treatment of Cushing's syndrome and is the treatment of choice for an adrenal adenoma, adrenocortical carcinoma, and primary adrenocortical hyperplasia. Furthermore, in selected cases, bilateral total adrenalectomy continues to be an alternative treatment for either Cushing's disease or ectopic ACTH syndrome.
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